Relapsing Forms of Multiple Sclerosis (RMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (GEMINI 1)

Relapsing Multiple Sclerosis Clinical Trial

— GEMINI 1  

Official title:

A Phase 3, Randomized, Double-blind Efficacy and Safety Study Comparing SAR442168 to Teriflunomide (Aubagio®) in Participants With Relapsing Forms of Multiple Sclerosis

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04410978
• Other study ID #: EFC16033
• Secondary ID: U1111-1238-14182
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: June 30, 2020
• Est. completion date: August 15, 2024

Study information

• Verified date: April 2024
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Primary Objective:

To assess efficacy of daily SAR442168 compared to a daily dose of 14 mg teriflunomide (Aubagio) measured by annualized adjudicated relapse rate (ARR) in participants with relapsing forms of MS

Secondary Objective:

To assess efficacy of SAR442168 compared to teriflunomide (Aubagio) on disability progression, MRI lesions, cognitive performance and quality of life To evaluate the safety and tolerability of daily SAR442168 To evaluate population pharmacokinetics (PK) of SAR442168 and relevant metabolites and its relationship to efficacy and safety To evaluate pharmacodynamics (PD) of SAR442168

Description:

Study duration will vary per participant in this event driven trial with a treatment duration of approximately 18 to 36 months. Participants completing the study will be offered to participate in a long term safety study.

Other known NCT identifiers

• NCT04964791

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 900
• Est. completion date: August 15, 2024
• Est. primary completion date: August 15, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

Inclusion criteria :

• The participant must be 18 to 55 years of age, inclusive, at the time of signing the informed consent

• The participant must have been diagnosed with RMS according to the 2017 revision of the McDonald diagnostic criteria

• The participant has an expanded disability status scale (EDSS) score =5.5 at the first Screening Visit

• The participant must have at least 1 of the following prior to screening:

• =1 documented relapse within the previous year OR

• =2 documented relapses within the previous 2 years, OR

• =1 documented Gd enhancing lesion on an MRI scan within the previous year

• Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies

• Male participants are eligible to participate if they agree to the following during the intervention period and until accelerated elimination procedure:

• Refrain from donating sperm

Plus either:

• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR

• Must agree to use contraception/barrier as detailed below:

Agree to use a male condom and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant

• A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions apply:

• Is not a WOCBP OR

• Is a WOCBP and agrees to use a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency, during the intervention period and until accelerated elimination procedure is completed (or for at least 10 days after the last dose of SAR442168, if the case was unblinded)

• A WOCBP must have a negative highly sensitive pregnancy test at screening and within 24hours before the first dose of study intervention.

• If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.

• The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.

• The participant must have given written informed consent prior to undertaking any study related procedure. This includes consent to comply with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. In countries where the legal age of maturity is greater than 18 years, a specific ICF for such legally minor participants must also be signed by the participant's legally authorized representative

Exclusion criteria:

• The participant has been diagnosed with primary progressive multiple sclerosis (PPMS) according to the 2017 revision of the McDonald diagnostic criteria or with nonrelapsing secondary progressive multiple sclerosis (SPMS)

• The participant has a history of infection or may be at risk for infection including but not limited to: HIV, transplantation, live attenuated vaccines, progressive multifocal leukoencephalopathy, tuberculosis, hepatitis B or C, any persistent chronic or active recurring infection

• Clinically significant laboratory abnormalities (including evidence of liver injury) or electrocardiogram abnormalities at Screening.

• The participant has conditions or situations that would adversely affect participation in this study, including but not limited to:

• A short life expectancy due to pre-existing health condition(s) as determined by their treating neurologist

• Medical condition(s) or concomitant disease(s) making them nonevaluable for the primary efficacy endpoint or that would adversely affect participation in this study, as judged by the Investigator

• A requirement for concomitant treatment that could bias the primary evaluation

• The participant has a history of or currently has concomitant medical or clinical conditions that would adversely affect participation in this study

• At screening, the participant is positive for hepatitis B surface antigen and/or hepatitis B core antibody and/or is positive for hepatitis C antibody

• The participant has any of the following:

• A bleeding disorder or known platelet dysfunction at any time prior to the screening visit

• A platelet count <150 000/µL at the screening visit

• The participant has a lymphocyte count below the lower limit of normal (LLN) at the screening visit

• The presence of psychiatric disturbance or substance abuse

• Prior/concomitant therapy

• The participant is receiving potent and moderate inducers of cytochrome P450 (CYP) 3A or potent inhibitors of CYP2C8 hepatic enzymes

• The participant is receiving anticoagulant/antiplatelet therapies

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Related Conditions & MeSH terms

• Multiple Sclerosis
• Relapsing Multiple Sclerosis
• Sclerosis

Intervention

Drug:
• Tolebrutinib
Pharmaceutical form: Tablet Route of administration: Oral
• Teriflunomide HMR1726
Pharmaceutical form: Tablet Route of administration: Oral
• Placebo to match Tolebrutinib
Pharmaceutical form: Tablet Route of administration: Oral
• Placebo to match Teriflunomide
Pharmaceutical form: Tablet Route of administration: Oral

Locations

Country	Name	City	State
Austria	Investigational Site Number :0400004	Linz
Belarus	Investigational Site Number :1120004	Vitebsk
Belarus	Investigational Site Number :1120005	Vitebsk
Bulgaria	Investigational Site Number :1000002	Pleven
Bulgaria	Investigational Site Number :1000005	Plovdiv
Bulgaria	Investigational Site Number :1000001	Sofia
Bulgaria	Investigational Site Number :1000004	Sofia
Bulgaria	Investigational Site Number :1000006	Sofia
Bulgaria	Investigational Site Number :1000008	Sofia
Bulgaria	Investigational Site Number :1000009	Sofia
Canada	Investigational Site Number :1240006	Gatineau	Quebec
Canada	Investigational Site Number :1240003	Ottawa	Ontario
Canada	Investigational Site Number :1240013	Toronto	Ontario
Canada	Investigational Site Number :1240016	Vancouver	British Columbia
China	Investigational Site Number :1560022	Baotou
China	Investigational Site Number :1560001	Beijing
China	Investigational Site Number :1560006	Beijing
China	Investigational Site Number :1560009	Beijing
China	Investigational Site Number :1560010	Beijing
China	Investigational Site Number :1560012	Beijing
China	Investigational Site Number :1560021	Beijing
China	Investigational Site Number :1560023	Beijing
China	Investigational Site Number :1560025	Beijing
China	Investigational Site Number :1560004	Changchun
China	Investigational Site Number :1560015	Changsha
China	Investigational Site Number :1560005	Chengdu
China	Investigational Site Number :1560019	Chongqing
China	Investigational Site Number :1560035	Fuzhou
China	Investigational Site Number :1560002	Guangzhou
China	Investigational Site Number :1560016	Guangzhou
China	Investigational Site Number :1560028	Guangzhou
China	Investigational Site Number :1560027	Hohhot
China	Investigational Site Number :1560042	Nanjing
China	Investigational Site Number :1560044	Nanjing
China	Investigational Site Number :1560003	Shanghai
China	Investigational Site Number :1560018	Shenyang
China	Investigational Site Number :1560014	Shijiazhuang
China	Investigational Site Number :1560008	Taiyuan
China	Investigational Site Number :1560020	Tianjin
China	Investigational Site Number :1560011	Wuhan
China	Investigational Site Number :1560017	Xi'an
China	Investigational Site Number :1560033	Yinchuan
Czechia	Investigational Site Number :2030004	Hradec Kralove
Czechia	Investigational Site Number :2030009	Pardubice
Czechia	Investigational Site Number :2030003	Teplice
Czechia	Investigational Site Number :2030007	Zlin
Denmark	Investigational Site Number :2080001	Esbjerg
Denmark	Investigational Site Number :2080005	Holstebro
Estonia	Investigational Site Number :2330001	Tallinn
Estonia	Investigational Site Number :2330002	Tartu
Finland	Investigational Site Number :2460003	Helsinki
Finland	Investigational Site Number :2460001	Tampere
Finland	Investigational Site Number :2460002	Turku
Germany	Investigational Site Number :2760001	Dresden
Germany	Investigational Site Number :2760019	Düsseldorf
Germany	Investigational Site Number :2760016	Hamburg
Germany	Investigational Site Number :2760008	Münster
Germany	Investigational Site Number :2760004	Rostock
Germany	Investigational Site Number :2760011	Ulm
Hong Kong	Investigational Site Number : 3440001	Shatin, NT
Italy	Investigational Site Number :3800011	Bergamo
Italy	Investigational Site Number :3800015	Catania
Italy	Investigational Site Number :3800012	Firenze
Italy	Investigational Site Number :3800014	Genova
Italy	Investigational Site Number :3800001	Milano
Italy	Investigational Site Number :3800010	Milano
Italy	Investigational Site Number :3800003	Napoli
Italy	Investigational Site Number :3800006	Napoli
Italy	Investigational Site Number :3800007	Orbassano	Torino
Italy	Investigational Site Number :3800008	Pavia
Italy	Investigational Site Number :3800002	Pozzilli	Isernia
Italy	Investigational Site Number :3800005	Roma
Italy	Investigational Site Number :3800009	Roma
Italy	Investigational Site Number :3800013	Roma
Japan	Investigational Site Number :3920014	Bunkyo-ku	Tokyo
Japan	Investigational Site Number :3920016	Chiba-shi	Chiba
Japan	Investigational Site Number :3920018	Kawagoe-shi	Saitama
Japan	Investigational Site Number :3920003	Kodaira-shi	Tokyo
Japan	Investigational Site Number :3920008	Koriyama-shi	Fukushima
Japan	Investigational Site Number :3920004	Moriguchi-shi	Osaka
Japan	Investigational Site Number :3920022	Morioka-shi	Iwate
Japan	Investigational Site Number :3920005	Niigata-shi	Niigata
Japan	Investigational Site Number :3920001	Osaka-shi	Osaka
Japan	Investigational Site Number :3920010	Ota-ku	Tokyo
Japan	Investigational Site Number :3920023	Sagamihara-shi
Japan	Investigational Site Number :3920013	Shinjuku-ku	Tokyo
Japan	Investigational Site Number :3920012	Tsukuba-shi	Ibaraki
Japan	Investigational Site Number :3920009	Ube-shi	Yamaguchi
Lithuania	Investigational Site Number :4400003	Kaunas
Lithuania	Investigational Site Number :4400002	Klaipeda
Lithuania	Investigational Site Number :4400004	Siauliai
Lithuania	Investigational Site Number :4400001	Vilnius
Mexico	Investigational Site Number :4840001	Mexico
Mexico	Investigational Site Number :4840002	Mexico
Mexico	Investigational Site Number :4840003	Veracruz
Poland	Investigational Site Number :6160003	Bydgoszcz	Kujawsko-pomorskie
Poland	Investigational Site Number :6160009	Glogow Mlp.	Podkarpackie
Poland	Investigational Site Number :6160002	Katowice	Slaskie
Poland	Investigational Site Number :6160004	Katowice	Slaskie
Poland	Investigational Site Number :6160001	Lodz
Poland	Investigational Site Number :6160008	Plewiska	Wielkopolskie
Poland	Investigational Site Number :6160005	Warszawa	Mazowieckie
Poland	Investigational Site Number :6160006	Warszawa	Mazowieckie
Romania	Investigational Site Number :6420015	Brasov
Romania	Investigational Site Number :6420008	Bucuresti
Romania	Investigational Site Number :6420004	Campulung
Romania	Investigational Site Number :6420003	Constanta
Romania	Investigational Site Number :6420010	Oradea
Romania	Investigational Site Number :6420005	Sibiu
Romania	Investigational Site Number :6420001	Targu Mures
Romania	Investigational Site Number :6420002	Timisoara
Russian Federation	Investigational Site Number :6430014	Krasnoyarsk
Russian Federation	Investigational Site Number :6430002	Moscow
Russian Federation	Investigational Site Number :6430008	Moscow
Russian Federation	Investigational Site Number :6430003	Nizhny Novgorod
Russian Federation	Investigational Site Number :6430011	Nizhny Novgorod
Russian Federation	Investigational Site Number :6430007	Pyatigorsk
Russian Federation	Investigational Site Number :6430012	Rostov-on-Don
Russian Federation	Investigational Site Number :6430005	Samara
Russian Federation	Investigational Site Number :6430009	Smolensk
Russian Federation	Investigational Site Number :6430001	St-Petersburg
Russian Federation	Investigational Site Number :6430006	Tyumen
Russian Federation	Investigational Site Number :6430004	Ufa
Spain	Investigational Site Number :7240009	Barcelona	Barcelona [Barcelona]
Spain	Investigational Site Number :7240004	Córdoba
Spain	Investigational Site Number :7240008	Donostia	Pais Vasco
Spain	Investigational Site Number :7240005	Málaga
Spain	Investigational Site Number :7240006	Murcia
Spain	Investigational Site Number :7240001	Pozuelo De Alarcón	Madrid
Spain	Investigational Site Number :7240003	Sevilla	Andalucia
Spain	Investigational Site Number :7240007	Valencia
Sweden	Investigational Site Number :7520001	Göteborg
Sweden	Investigational Site Number :7520002	Stockholm
Taiwan	Investigational Site Number :1580007	Hsinchu City
Taiwan	Investigational Site Number :1580005	Kaohsiung
Taiwan	Investigational Site Number :1580003	Taichung
Taiwan	Investigational Site Number :1580002	Taipei
Taiwan	Investigational Site Number :1580006	Taoyuang
Turkey	Investigational Site Number :7920005	Eskisehir
Turkey	Investigational Site Number :7920011	Hatay
Turkey	Investigational Site Number :7920002	Istanbul
Turkey	Investigational Site Number :7920003	Istanbul
Turkey	Investigational Site Number :7920007	Istanbul
Turkey	Investigational Site Number :7920009	Istanbul
Turkey	Investigational Site Number :7920008	Izmir
Turkey	Investigational Site Number :7920010	Izmir
Turkey	Investigational Site Number :7920001	Kocaeli
Turkey	Investigational Site Number :7920006	Mersin
Ukraine	Investigational Site Number :8040011	Ivano-Frankivsk
Ukraine	Investigational Site Number :8040013	Kharkiv
Ukraine	Investigational Site Number :8040016	Kharkiv
Ukraine	Investigational Site Number :8040008	Kherson
Ukraine	Investigational Site Number :8040014	Kyiv
Ukraine	Investigational Site Number :8040010	Lutsk
Ukraine	Investigational Site Number :8040001	Lviv
Ukraine	Investigational Site Number :8040009	Odesa
United States	University of Colorado-Site Number:8400012	Aurora	Colorado
United States	University of Alabama MS Center-Site Number:8400013	Birmingham	Alabama
United States	Tufts Medical Center-Site Number:8400072	Boston	Massachusetts
United States	Optimed Research, LTD-Site Number:8400147	Columbus	Ohio
United States	The Ohio State University Wexner Medical Center-Site Number:8400150	Columbus	Ohio
United States	University of Texas Southwestern Medical Center-Site Number:8400077	Dallas	Texas
United States	Michigan Institute For Neurological Disorders-Site Number:8400058	Farmington Hills	Michigan
United States	Beth Israel Deaconess Medical Center-Site Number:8400064	Fort Myers	Florida
United States	Consultants In Neurology-Site Number:8400011	Northbrook	Illinois
United States	Oklahoma Medical Research Foundation-Site Number:8400018	Oklahoma City	Oklahoma
United States	The Memorial Hospital-Site Number:8400033	Owosso	Michigan
United States	Sharlin Health & Neurology-Site Number:8400093	Ozark	Missouri
United States	Providence Multiple Sclerosis Center-Site Number:8400020	Portland	Oregon
United States	Meridian Clinical Research, LLC-Site Number:8400005	Raleigh	North Carolina
United States	Missouri Baptist Medical Center-Site Number:8400019	Saint Louis	Missouri
United States	University of San Francisco, Sandler Neurosciences Center-Site Number:8400137	San Francisco	California
United States	Meridian Clinical Research-Site Number:8400003	Savannah	Georgia
United States	Multiple Sclerosis Center, Swedish Neuroscience Institute-Site Number:8400121	Seattle	Washington
United States	Axiom Clinical Research of Florida-Site Number:8400001	Tampa	Florida
United States	University of South Florida-Site Number:8400006	Tampa	Florida
United States	Georgetown University Medical Center-Site Number:8400119	Washington	District of Columbia
United States	Columbus Neuroscience-Site Number:8400010	Westerville	Ohio
United States	Wake Forest University Baptist Medical Center-Site Number:8400116	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Sanofi

Countries where clinical trial is conducted

United States,  Austria,  Belarus,  Bulgaria,  Canada,  China,  Czechia,  Denmark,  Estonia,  Finland,  Germany,  Hong Kong,  Italy,  Japan,  Lithuania,  Mexico,  Poland,  Romania,  Russian Federation,  Spain,  Sweden,  Taiwan,  Turkey,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Annualized Adjudicated Relapse Rate : Number of confirmed adjudicated protocol defined relapses	Annualized Adjudicated Relapse Rate : Number of confirmed adjudicated protocol defined relapses	Up to approximately 36 months
Secondary	Time to onset of confirmed disability worsening confirmed over at least 6 months	Time to onset of confirmed disability worsening (CDW), confirmed over at least 6 months, defined as follows: increase of =1.5 points from the baseline expanded disability status scale (EDSS) score when the baseline score is 0 OR; increase of =1.0 point from the baseline EDSS score when the baseline score is 0.5 to =5.5 OR; increase of =0.5 point from the baseline EDSS score when the baseline score is >5.5 - 5.	Up to approximately 36 months
Secondary	Time to onset of CDW, assessed by the EDSS score and confirmed over at least 3 months		Up to approximately 36 months
Secondary	Total number of new and/or enlarging T2 hyperintense lesions as detected by MRI from Month 6 through the end of study (EOS)		From 6 months up to approximately 36 months
Secondary	Total of Gd-enhancing T1 hyperintense lesions as detected by MRI from 6 months through the EOS		From 6 months up to approximately 36 months
Secondary	Change in cognitive function	Change in cognitive function from baseline to the end of study (EOS) as assessed by SDMT and by CVLT-II where available	From Baseline up to approximately 36 months
Secondary	Time to confirmed disability improvement	Time to confirmed disability improvement (CDI), defined as a =1.0 point decrease on the EDSS from the baseline EDSS score confirmed over at least 6 months	From Baseline up to approximately 36 months
Secondary	Percent Change in Brain volume loss (BVL)	Brain volume loss (BVL) rate as detected by brain MRI from Month 6 to the EOS	From 6 months up to approximately 36 months
Secondary	Change in Multiple Sclerosis Quality of Life	Change in Multiple Sclerosis Quality of Life-54 (MSQoL-54) from the baseline through the EOS	From Baseline up to approximately 36 months
Secondary	Number of participants with adverse events A(Es) leading to permanent study intervention discontinuation, and adverse events of special interest (AESI)		From screening until end of study approximately 36 months
Secondary	Population Pharmacokinetics - Concentration SAR442168 and relevant metabolites at 6 months	Plasma concentration of SAR442168 (population PK assessment) at 6 Months	6 Months
Secondary	Population Pharmacokinetics Concentration of SAR442168 and relevant metabolites at 9 Months	Plasma concentration of SAR442168 (population PK assessment) at 9 Months	9 Months
Secondary	Population Pharmacokinetics - Concentration of SAR442168 and relevant metabolites at 12 Months	Plasma concentration of SAR442168 (population PK assessment) at 12 Months	12 Months
Secondary	Change in plasma NfL	Change in plasma neurofilament light chain (NfL) levels at the EOS compared to baseline	From Baseline until end of study approximately 36 months
Secondary	Change in lymphocyte Phenotype	Change in lymphocyte phenotype subsets in whole blood at the EOS compared to baseline in a subset of participants	From Baseline until end of study approximately 36 months
Secondary	Changes in plasma Immunoglobulin levels	Changes in serum immunoglobulin level at the EOS compared to baseline	From Baseline until end of study (up to 36 months)
Secondary	Change in CHI3L1 levels	Change in serum Chi3L1 levels at the EOS compared to baseline	From Baseline until end of study approximately 36 months